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Kobeissy FH, editor. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press/Taylor & Francis; 2015.

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Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects.

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Chapter 5Oxidative Stress, Brain Edema, Blood–Brain Barrier Permeability, and Autonomic Dysfunction from Traumatic Brain Injury

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Traumatic brain injury (TBI) contributes to a substantial number of deaths and cases of permanent disability annually. An immune response to head injury gives a timeline to the pathological cascades with multiple cellular, metabolic and immune pathways activated from the moment of injury. In addition to the primary brain injury which refers to an unavoidable brain damage that occurs at the immediate moment of impact, secondary brain injury develops in the latter term, progressively contributing to the worsened neurological outcome. This complex phenomenon is defined by the various neurochemical cascades activated, and the systemic physiological responses which manifest in the afterwards the traumatic event. Microglial activation and macrophage accumulation after diffuse brain injury is observed within 6 to 48 hours post injury. Thus, diffuse brain injury mediated immune responses, blood-brain barrier alterations, oxidative stress and neuroinflammation seem to play an important role in the pathology.


TBI is the leading cause of death and disability in children and adults from ages 1 to 44. Brain injuries are most often caused by motor vehicle crashes, sports injuries, or simple falls on the playground at work or in the home. Every year, approximately 52,000 deaths result from traumatic brain injury. An estimated 1.5 million head injuries occur every year in the United States, varying from mild to severe. The incidence of sports-related TBIs is estimated between 1.6 and 3.8 million. At least 5.3 million Americans, 2% of the U.S. population, currently live with disabilities resulting from TBI (Langlois, 2006). Long-term effects of TBI can lead to cardiovascular and neurological disorders such as Parkinsonism, Alzheimer disease, dementia, sleep disturbances, anxiety, abnormalities in pain sensation, and muscular dysfunction (Kobeissy, 2014).

Over the past several decades, numerous experimental animal models have been implemented to study the mechanisms of TBI (i.e., overpressure blast injury, controlled cortical impact, and the fluid percussion models). These animal models have been well characterized with predictable neurological, histological, and physiological changes similar to those observed in clinical brain injury and help us to determine the underlying mechanisms of acute injury and establish treatment strategies.

Studies demonstrated that in addition to the primary physical impact of the injury, TBI leads to progressive pathophysiological changes, resulting in a reduction in brain–blood flow and a decrease in tissue oxygen levels leading to ischemia, subsequent secondary injury, blood–brain barrier breakdown, and brain edema (Unterberg et al., 2004). Death of resident cells of the central nervous system (CNS) has traditionally been accepted to take place in two phases: an early necrotic and an ongoing long-term apoptotic phase. Secondary brain injury develops in minutes to months after the original insult, progressively contributing to the worsened neurological impairment. This complex phenomenon is defined by the activation of various neurochemical cascades and the systemic physiological responses that manifest after the traumatic event (Morganti-Kossmann et al., 2007; Werner, 2009). At the cellular level, the biphasic nature of secondary injury is mediated by numerous disturbed pathways that include (1) excitotoxicity caused by an excess of the neurotransmitter glutamate; (2) free-radical generation by mitochondrial dysfunction, causing damage to proteins and phospholipid membranes of neurons and glia; and (3) the neuroinflammatory response that takes place because of both CNS and systemic immunoactivation as shown in Figure 5.1.

FIGURE 5.1. Mechanisms of brain injury.


Mechanisms of brain injury. Brain injury leads to local-systemic secondary changes besides the primary (physical) injury. Failure of the transport system and disturbances in microvascular circulation causes an edema that exacerbates the blood–brain (more...)


Although the primary injury occurs by the physical impact of the trauma, the tissue injury augmented by the secondary injury. The brain is quite sensitive to free radical damage, although it is secured by the blood–brain barrier (BBB). The high rate of oxidative metabolism in the brain and its elevated levels of polyunsaturated lipids, which are the target of lipid peroxidation, render it particularly vulnerable to oxidative stress.

Previous studies have demonstrated that reactive oxygen species (ROS) such as the superoxide radicals and nitric oxide can form peroxynitrite, a powerful oxidant that impairs cerebral vascular function after TBI (DeWitt and Prough, 2009; Vuceljic et al., 2006). Thus trauma impairs the oxygenation of brain from impaired circulation and ischemia. The reperfusion state after the trauma enables the vitality of the neurons but also increases the amount of ROS generated (Ansari et al., 2008; Cornelius, 2013; Readnower et al., 2010). The generation of free oxygen radicals, superoxide, hydrogen peroxide, nitric oxide, and peroxynitrite cause excitotoxicity and impair the energy metabolism of the cells. The endogenous antioxidant system (i.e., glutathione peroxidase, superoxide dismutase, catalase, and uric acid) aims to convert/neutralize these ROS to less toxic derivatives, thus preventing binding of these to the macromolecules like DNA, RNA, or proteins (Figure 5.2). However, the excessive amount of ROS produced depletes the endogenous antioxidants and the increased peroxidation of membrane lipids or oxidation of proteins lead to DNA fragmentation and inhibits the mitochondrial electron transport system. This process induces apoptosis or necrosis (Tran, 2014).

FIGURE 5.2. Oxidative stress and the endogenous antioxidant system.


Oxidative stress and the endogenous antioxidant system. Brain injury causes an increase in oxidative stress. The generated reactive oxygen species have an uncoupled electron and may bind to macromolecules or cause damage in protein or lipid structures (more...)

Because the role of oxidative stress in TBI is shown in different models, a number of therapeutic trials based on the ability of antioxidants to scavenge free radicals have been attempted in both experimental and clinical TBI. Melatonin, alpha tocopherol, ascorbic acid, Tempol, Edaravone, resveratrol, alpha lipoic, and N-acetylcysteine acid have been widely used to protect the brain tissue against TBI-induced oxidative stress (Slemmer, 2008).


Brain edema leading to an expansion of brain volume has a crucial impact on morbidity and mortality after TBI because it increases intracranial pressure, impairs cerebral perfusion and oxygenation, and contributes to additional ischemic injuries (Kempski, 2001; Unterberg et al., 2004).

Different types of brain edema and their characteristics are summarized in Table 5.1.



Types of Brain Edema and Their Characteristics

Failure of ion pumps, BBB disruption, neuroinflammation, and oxidative damage are among the major mechanisms that play important roles in the development of cerebral edema after TBI. Generation of free radicals and hypoxia leads to the failure of the Na+-K+-ATPase, a membrane-bound enzyme required for cellular transport. Dysfunction of this pump is a common feature in CNS pathologies related to ischemic conditions and TBI. The activity of Na+-K+-ATPase pump is very sensitive to free radical reactions and lipid peroxidation. Reductions in this activity can indicate membrane damage indirectly. Thus Na+-K+-ATPase is clearly downregulated under low-oxygen conditions that in turn triggers brain edema and enhances the loosening of tight junctions and BBB breakdown. Myeloperoxidase activity, an index for neutrophil infiltration, also increases as evidence of inflammation (Biber et al., 2009). Antiinflammatory agents and antioxidants have both been shown to exert beneficial effects in decreasing tissue injury, but most of them fail to prevent edema formation (Hakan et al, 2010).


Diffuse brain injury–mediated immune response; edema, BBB alterations, and neuroinflammation seem to play an important role in the pathology. Microglial activation within the injured area is observed within 6 to 48 hours postinjury. Edema and the increase in BBB permeability were shown to occur immediately after the injury in closed-head injury studies (Ersahin et al., 2010). It was also shown to recover by the third day after the blast exposure (Readnower et al., 2010; Abdul-Muneer et al., 2013). There are several factors (i.e. inflammatory mediators, free radicals, proteases, adhesion molecules, AQP4, VEGF, bradykinin, and arachidonate metabolites) that enhance edema formation and BBB dysfunction (Unterberg et al., 2004). After a blast injury, loosening of the vasculature and perivascular unit was mediated by the activation of matrix metalloproteinases and fluid channel aquaporin-4, promoting edema, enhanced leakiness of the BBB, and progression of neuroinflammation and neuronal degeneration (Abdul-Muneer et al., 2013). Although many studies demonstrate a similar pathophysiologic progression as the conventional TBI, a recent study reported that cerebrovascular injury from a primary blast is distinct from it, suggesting that BBB disruption in blast injury was acute, not resulting from a delayed inflammation as it does in the conventional disruption (Yeoh et al., 2013).

Therapies targeting the restoration of BBB provide the brain homeostasis. Potential agents may be directed to reduce the expression of cell adhesion molecules and/or interfere with signaling of neuroinflammatory mediators of the endothelium. Also neurotrophic factors, such as brain-derived neurotrophic factor and nerve growth factor, can potentially have beneficial effects on functional recovery after injury (Chodobski et al., 2011).


One deleterious consequence of brain injury is autonomic nervous system dysregulation and/or dysautonomia. Autonomic nervous system dysfunction has been documented after TBI, but is not well understood. Ninety percent of TBI patients demonstrate signs of autonomic dysfunction during the first week after injury, with about one-third of the patients developing longer lasting autonomic dysfunction. Autonomic dysregulation is characterized by distinct changes in cardiovascular hyperactivity, sleep function, and specific biomarkers of neural damage. System dysregulation might lead to a range of comorbidities such as hypertension, endothelial dysfunction, and end-organ perfusion abnormalities. Specifically, TBI disruption of autonomic function most often results in sustained sympathoactivation. This sympathetic hyperactivity after TBI remains poorly understood, although sympathetic hyperactivity likely contributes to the high morbidity and mortality associated with TBI. Sympathetic hyperactivity contributes to systemic stress, including neuroinflammation and oxidative stress in the autonomic nervous system. Eventually these disturbances lead to cardiovascular dysfunction (Cernak, 2010) and sleep complications (Viola-Saltzman and Watson, 2012). Systemic stress is associated with activation of the hypothalamic-pituitary-adrenal axis and the hypothalamic sympathoadrenal medullary axis. It is known that TBI activates the hypothalamic-pituitary-adrenal axis (Mcintosh, 1994); however, little is known regarding the TBI-induced activation of the sympathoadrenal medullary axis, and there are limited therapeutic options to treat this sympathoactivation.

We recently demonstrated selective biochemical markers of autonomic function and oxidative stress in male Sprague Dawley rats subjected to head-directed overpressure insult (Tümer et al., 2013). There were increased levels of tyrosine hydroxylase, dopamine-β hydroxylase, and neuropeptide Y in the adrenal medulla along with plasma norepinephrine. In addition, overpressure blast injury (OBI) significantly elevated tyrosine hydroxylase in the nucleus tractus solitarius of the brain stem, whereas AT1 receptor expression and NADPH oxidase activity, a marker of oxidative stress, was elevated in the hypothalamus suggesting that single OBI exposure results in increased sympathoexcitation (Figure 5.3). The mechanism may involve the elevated AT1 receptor expression and NADPH oxidase levels in the hypothalamus. Taken together, such effects may be important factors contributing to pathology of brain injury and autonomic dysfunction associated with the clinical profile of patients after OBI (Tumer et al., 2013). However, insufficient published data are available to describe the long-term effects of TBI on central noradrenergic systems, particularly on neuroplastic adaptations within numerous targets of central noradrenergic projections. In addition, understanding the etiology of these changes may shed new light on the molecular mechanism(s) of injury, potentially offering new strategies for treatment.

FIGURE 5.3. Brain injury and the sympathetic nervous system.


Brain injury and the sympathetic nervous system. Brain injury increases the sympathetic nervous system (SNS) tonus as a result of the increased norepinephrine (NE) turnover. The levels of the biosynthetic enzymes (i.e., tyrosine hydroxylase [TH], dopamine (more...)


Recent studies are under way on the basilar artery function. Preliminary results showed that OBI impaired the vascular reactivity of the basilar artery. OBI resulted in an increase in the contractile responses to endothelin and a decrease in the relaxant responses to acetylcholine after single or repeated exposure to injury. However, impaired Diethylamine NONO-ate induced dilation and increased arterial wall thickness/lumen ratio were observed only in the repeated injury group (Toklu et al., 2014).


Individuals identified with apparent brain pathology (e.g., edema, hemorrhage, seizures) are well recognized and provided symptomatic treatment. However, the lack of conclusive physical evidence, especially in mild TBI, may not adequately be diagnosed with standard assessment tools. Physical symptoms may resolve rapidly. On the other hand, subtle changes in brain may occur that lead to neurological disorders and cognitive impairment long after the recovery of the primary injury.

Although most of the studies address the acute treatment of TBI, their efficiency in the long term is not clear. Therefore, further studies are needed to elucidate the mechanisms of secondary injury and long-term changes in the brain metabolism and physiological function.


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© 2015 by Taylor & Francis Group, LLC.
Bookshelf ID: NBK299195PMID: 26269897


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